Open AccessJournal Article
Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content.
Wai Kwong Eng,F. L. Mccabe,K. B. Tan,M R Mattern,G. A. Hofmann,R. D. Woessner,R. P. Hertzberg,Randall K. Johnson +7 more
TLDR
The results suggest that development of resistance to inhibitors of topoisomerase I can occur by down-regulation of the target enzyme, thus reducing the production of lethal enzyme-mediated DNA damage.Abstract:
A camptothecin-resistant subline of P388 leukemia (P388/CPT) was developed by repeated transplantation of P388 cells in mice treated with therapeutic doses of camptothecin. In mice bearing the resistant tumor, a maximally tolerated dose of camptothecin produced no net reduction in tumor cell burden, in contrast to a 5-log cell kill in the parental P388 (P388/S). The IC50 of camptothecin, as determined by colony formation assays of cultured cells, was 8 times greater for the cloned P388/CPT cell line than for P388/S. P388/CPT cells were not cross-resistant to other antineoplastic agents, including topoisomerase II inhibitors. The type I topoisomerases purified from P388/CPT and P388/S cells were identical with respect to molecular weight, specific activity, in vitro camptothecin sensitivity, and DNA cleavage specificity. Camptothecin induced fewer protein-associated DNA single-strand breaks in the resistant cells than in the wild-type P388 cells. Topoisomerase I mRNA, immunoreactivity, and extractable enzymatic activity were 2-4 times lower for P388/CPT cells than for P388/S cells. As resistance to camptothecin developed, topoisomerase I extractable activity decreased, concomitant with an increase in topoisomerase II extractable activity. Furthermore, the appearance of camptothecin resistance was associated with specific rearrangements of the topoisomerase I gene. These results suggest that development of resistance to inhibitors of topoisomerase I can occur by down-regulation of the target enzyme, thus reducing the production of lethal enzyme-mediated DNA damage. The enhanced topoisomerase II activity in these cells suggests that resistance to camptothecin may be overcome by co-treatment with topoisomerase II inhibitors.read more
Citations
More filters
Journal ArticleDOI
DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.
TL;DR: This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors and discusses the common mechanism of action ofTopoisomerase poisons by interfacial inhibition and trapping of topisomerase cleavage complexes.
Journal Article
Intracellular Roles of SN-38, a Metabolite of the Camptothecin Derivative CPT-11, in the Antitumor Effect of CPT-11
TL;DR: The results indicate that CPT-11 itself possesses a marginal antiproliferative effect but that SN-38 plays an essential role in the mechanism of action of C PT-11.
Journal Article
Current Perspectives on the Clinical Experience, Pharmacology, and Continued Development of the Camptothecins
TL;DR: Preliminary results suggest that irinotecan may have an increasing role in the treatment of other solid tumors, including small and non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer, and malignant gliomas.
Journal ArticleDOI
Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time of Leukemic Relapse
Scott H. Kaufmann,Judith E. Karp,Phyllis A. Svingen,Stan Krajewski,Philip J. Burke,Steven D. Gore,John C. Reed +6 more
TL;DR: In this paper, the authors examined the cellular levels of four related intracellular polypeptides that have been implicated as negative regulators of apoptosis in acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) cell lines.
Journal ArticleDOI
Phase I and pharmacokinetic trial of weekly CPT-11
Mace L. Rothenberg,J. G. Kuhn,Howard A. Burris,James F. Nelson,John R. Eckardt,M Tristan-Morales,Susan G. Hilsenbeck,Geoffrey R. Weiss,Lon Smith,G. I. Rodriguez +9 more
TL;DR: The maximum-tolerated dose (MTD) for CPT-11 in this patient population was 150 mg/m2/wk when administered on a weekly-times-four schedule repeated every 6 weeks and Grade 4 diarrhea was the dose-limiting toxicity (DLT) at the 180-mg/m 2/wk dose level.